a) Field of the Invention
The present invention relates to instruments and methods for the spectrophotometric determination of glucose in the aqueous humor of the eye and the estimation of the level of glucose in the blood based on the values thus obtained.
b) Background Art
An important aspect in the treatment of diabetes is the frequent determination of the blood glucose level of the patient so as to manage food intake and the dosage and timing of insulin injections. Presently, blood glucose analyzers for home use by the patient require lancing of the finger to obtain a drop of blood. The blood is placed on a strip containing reagents which react with glucose to form a chromophor which is then read by a reflectance colorimeter within the analyzer. This procedure is painful and it may result in infections which are particularly hazardous to diabetic persons. In addition, the annual cost of reagent strips can range from several hundred to over one thousand dollars per year per patient.
Non-invasive in vivo determination of blood constituents by near-infrared spectroscopy was first applied to oximetry, the determination of the oxygen content of the blood based on the spectral characteristics of hemoglobin and oxyhemoglobin. Wood (U.S. Pat No. 2,706,927) described a method using two wavelengths of light. Shaw (U.S. Pat. No. 3,638,640) improved this procedure by using more wavelengths of light. This technique was made significantly more practical by use of the modulation caused by the pulse as invented in 1972 by Aoyagi (Japanese Application 947714, April 1979). Improvements were described by Nielsen (U.S. Pat No. 4,167,331) and Flower (U.S. Pat. No. 4,863,265). This pulse oximetry technique is in routine clinical use. Jobsis (U.S. Pat. No. 4,223,680), Chance, Ferrari, Hazeki, Seiyama, Tamura, Takada and coworkers have applied spectrophotometric techniques to the in vivo determination of oxygen in the brain and other tissues. Research in this area continues. Relevant publications include: Chance Bet al., "Comparison of time-resolved and -unresolved measurements of deoxyhemoglobin in brain", Proc. Natl. Acad. Sci. USA 85: 4971-4975; Ferrari Met al., "Continuous non-invasive monitoring of human brain by near-infrared spectroscopy", Adv Exp Med Biol 191:873-882 (1985); Hazeki O et al., "Near-infrared spectrophotometric monitoring of haemoglobin and cytochrome a,a.sub.3 in situ" Adv Exp Med Biol 215: 283-289 (1987); Seiyama A et al., "Simultaneous Measurement of Haemoglobin oxygenation of brain and skeletal muscle of rat in vivo by near-infrared spectrophotometry", Adv Exp Med Biol 215: 291-295 (1987); Tamura Met al., "Spectroscopic characteristics of rat skeletal and cardiac tissues in the visible and near-infrared region", Adv Exp Med Biol 215:297-300 (1987); Takada M et al., "Non-invasive near-infrared measurements of human arm tissues in vivo", Adv Exp Med Biol 215:301-304 (1987); Ferrari M et al., "Determination of cerebral venous hemoglobin saturation by derivative near-infrared spectroscopy" Adv Exp Med Biol 248:47-53 (1989).
Various workers have attempted to use near-infrared spectroscopy for the in vitro or in vivo characterization of tissue for malignancy including Rosenthal (U.S. Pat No. 4,017,192), who suggested in vitro examination, and Stoddart (U.S. Pat. Nos. 4,570,638, 4,725,147, and 4,817,623), who described an in vivo method and apparatus. To date these methods do not appear generally useful.
The use of in vivo spectrophotometric measurements for the non-invasive transcutaneous determination of glucose was described by Dahne and Cross (U.S. Pat. No. 4,655,225) using typically two wavelengths of near-infrared light in the range from 1000 to 2700 nanometers. Investigations by Peura and Mendelson were reported by Schrady in February 1985. Schrady N, "The view from a distance; advances in optics and electronics are allowing physicians to glean diagnostic information without drawing blood", Forbes 135 (2): 142 (1985). Schmidtke (DE 3541165, EP 226822) described a three-wavelength device for measurement of glucose through the ear lobe using interference filters at 805, 1300, and 1600 nanometer wavelengths and optical modulation at different frequencies to separate the information. Rosenthal (U.S. Pat. No. 5,028,787) describes a system for in vivo measurement of glucose in blood using transmission or interaction at least one pair of wavelengths in the spectral region between 600 and 1100 nanometers. Robinson (U.S. Pat. No. 4,975,581) describes methods and apparatus means for the determination of an analyte in biological fluid samples characterized by the algorithm and mathematical calibration model used to calculate unknown concentrations of the analyte. NASA has supported SBIR Phase 1 and Phase 2 programs in "Non-invasive blood analysis during manned space flight" under contract 90-1-12.02-1545 with Boston Advanced Technologies. To date, while the results are promising, none of these approaches has reached the level of precision and accuracy necessary for effective monitoring of blood glucose levels in vivo, largely due to the interferences from other blood constituents, notably hemoglobin in the 600 to 1100 nanometer region, and from various tissue components. In addition, the pulse and movements by the patient during measurement add temporal variations to the measurements.
March (U.S. Pat. Nos. 3,958,560 and 4,014,321) suggested the measurement of optical rotation to determine the glucose concentration in the aqueous humor of the eye which was then related to the blood glucose level of the patient. However, miniaturization and attachment of the measurement device to the eye in similar fashion to a contact lens proved impractical. However, Reim and March provide evidence that the glucose level in the aqueous humor is related to that in the blood and the lag time between blood glucose changes and aqueous humor concentrations is sufficiently short to allow monitoring of blood glucose via measurements on aqueous humor.
It is, accordingly, an object of the present invention to provide a new and improved apparatus for and method of using near-infrared energy for the determination of glucose concentration in the blood based on measurements made of the aqueous humor of the eye.